Absence of Melatonin Induces Night-Time Hepatic Insulin Resistance and Increased Gluconeogenesis Due to Stimulation of Nocturnal Unfolded Protein Response

Abstract

It is known that the circadian rhythm in hepatic phosphoenolpyruvate carboxykinase expression (a limiting catalytic step of gluconeogenesis) and hepatic glucose production is maintained by both daily oscillation in autonomic inputs to the liver and night feeding behavior. However, increased glycemia and reduced melatonin (Mel) levels have been recently shown to coexist in diabetic patients at the end of the night period. In parallel, pinealectomy (PINX) is known to cause glucose intolerance with increased basal glycemia exclusively at the end of the night. The mechanisms that underlie this metabolic feature are not completely understood. Here, we demonstrate that PINX rats show night-time hepatic insulin resistance characterized by reduced insulin-stimulated RAC-α serine/threonine-protein kinase phosphorylation and increased phosphoenolpyruvate carboxykinase expression. In addition, PINX rats display increased conversion of pyruvate into glucose at the end of the night. The regulatory mechanism suggests the participation of unfolded protein response (UPR), because PINX induces night-time increase in activating transcription factor 6 expression and prompts a circadian fashion of immunoglobulin heavy chain-binding protein, activating transcription factor 4, and CCAAT/enhancer-binding protein-homologous protein expression with Zenith values at the dark period. PINX also caused a night-time increase in Tribble 3 and regulatory-associated protein of mammalian target of rapamycin; both were reduced in liver of PINX rats treated with Mel. Treatment of PINX rats with 4-phenyl butyric acid, an inhibitor of UPR, restored night-time hepatic insulin sensitivity and abrogated gluconeogenesis in PINX rats. Altogether, the present data show that a circadian oscillation of UPR occurs in the liver due to the absence of Mel. The nocturnal UPR activation is related with night-time hepatic insulin resistance and increased gluconeogenesis in PINX rats.

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…Finally, Nogueira and colleagues determined that surgical removal of the pineal (i.e. pinealectomy [PINX]) from mice shifted the endogenous rhythm of RAC-alpha serine/threonine-protein kinase (Akt) phosphorylation (a marker of insulin receptor activity) and disrupted the acute liver response to insulin [104]. Although they did not examine clock gene expression, they did find that PINX altered the timing and amplitude of the known clock-regulated genes, Pepck (also known as Pck1) and Foxo1.…”

Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats

“…On the other hand, melatonin supplementation can improve the glucose intolerance induced by high-fat and high-fructose diets (16,33). Previously, we have reported the ability of melatonin to control gluconeogenesis in experiments that showed that surgical ablation of the pineal gland reduced glucose clearance after pyruvate load (23). Corroborating our present hypothesis that melatonin may suppress gluconeogenesis due to its action in the central nervous system, a previous study demonstrated that intracranial rather than intraperitoneal injections of melatonin effectively suppressed the hyperglycemic response to the intracranial injection of 2-deoxy-D-glucose (35).…”

“…Total RNA was extracted from ϳ100 mg of liver using Trizol reagent. Total RNA was reverse transcribed, as described previously (23).…”

“…In vivo and in vitro experiments have demonstrated that melatonin also plays a role in energy homeostasis by regulating body mass and adiposity and leptin expression by adipocytes (1,40). Glucose homeostasis is also altered by the absence of melatonin in such a way that pinealectomized rats display glucose intolerance and desynchronized circadian pattern of gluconeogenesis, hallmarked by increased nighttime glucose levels (17,18,23). Moreover, chronic melatonin administration has been shown to improve glucose homeostasis not only in pinealectomized rats but also in rats rendered insulin resistant by diet manipulation (16,33,34).…”

The role of melatonin in development of gestational diabetes mellitus

“…В эксперименте показано, что в резуль-тате удаления эпифиза в чувствительных к ин-сулину тканях (белая и бурая жировая ткань, скелетные и сердечная мышцы) резко снижает-ся содержание ГЛЮТ4 мРНк (GLUT4 mRnA), микросомального и мембранного протеина. кроме того, в отсутствие мелатонина наруша-ется функция инсулиновых рецепторов, в част-ности МТ2 в адипоцитах жировой ткани, что резко снижает захват глюкозы этими клетками [60,61]. Выявленные эффекты пинеалэктомии исчезали в результате терапии мелатонином [62,63].…”